Cocaine inhibition of dopamine, norepinephrine, and serotonin transporters is responsible for the addictive properties of this potent illicit compound. A molecular model of the cocaine neurotransmitter transporter complex would promote understanding of the addictive nature of cocaine and accelerate development of therapeutics for psychiatric treatment of cocaine addiction. Recent developments in the neurotransmitter transporter field present a unique opportunity to develop an accurate model of cocaine interactions with neurotransmitter transporters. The recent report of a high-resolution crystal structure of a leucine transporter, the first member in the neurotransmitter sodium symporter (NSS) family of proteins, enables reliable structural interpretation of functional data for human dopamine, norepinephrine, and serotonin transporters. This structure, combined with the currently available sequences for the NSS family and the datasets for cocaine-derived inhibitors of serotonin and dopamine transporters, give the means to create an accurate model for cocaine neurotransmitter transporter interactions. This project takes a two-pronged approach to modeling the cocaine neurotransmitter complexes. First, evolutionary conserved structural and functional constraints evolutionary will be extracted using "evolutionary trace" and "statistical coupling analysis" methods on available neurotransmitter transporter sequences. This will identify networks of residues responsible for the diverse functionalities observed in neurotransmitter transporters. Second, protein computational modeling techniques will be used to build comparative models off the leucine transporter structure, and then to predict modes of interaction for cocaine and cocaine analogs. The models can then be filtered and refined based on available biological data. Out of this project, the resulting atomic resolution models of cocaine and its analogs bound to dopamine and serotonin transporter will explain and predict the efficacy of new therapeutics for treatment of cocaine addiction. In short, the molecular models of cocaine bound to serotonin or dopamine transporter would provide a critical advancement for investigating and understanding cocaine and its neuro-chemical effects.